ABSTRACT Neuregulin-1 (NRG-1) is a growth factor which plays a crucial role in regulation of adult heart adaptation to physiological and pathological stress acting via ERBB receptors. Most of the research on the role of NRG-1 in the heart has focused on its effects on cardiomyocytes. Our preliminary studies, however, suggest an important role for NRG-1 and ERBB3 receptors in myeloid mononuclear cells (monocytes and macrophages). We found that neuregulin signaling in these cells contributes to resolution of inflammation by promoting the functional shift from cytokine-secreting ?pro-inflammatory? cells towards a phagocytic ?pro-resolution? phenotype. In Specific Aim 1 we will test the hypothesis that NRG-1, acting via ERBB3 receptors, restricts inflammation, targeting myeloid cells that infiltrate the myocardium after an ischemic injury. In Specific Aim 2, we will determine molecular mechanisms involved in NRG-1-dependent regulation of phagocytic function of myeloid mononuclear cells. Finally, in Specific Aim 3, we will determine if inhibition of A2B adenosine receptors leads to an up-regulation of ERBB receptors and potentiates the beneficial effect of neuregulin after MI. These studies will greatly enhance our understanding of myeloid cell-specific neuregulin signaling in the regulation of inflammatory cell responses and may result in the development of novel therapeutic approaches to treat diseases associated with inflammation, including but not limited to ischemic heart injury.